Location: Animal Disease Research
Project Number: 2090-32000-035-001-A
Project Type: Cooperative Agreement
Start Date: Aug 1, 2015
End Date: Jul 31, 2020
Objective:
The intracellular bacteria Coxiella burnetii is a cause of abortion in ruminants (cattle, sheep and goats). It is also the cause of Q fever in humans, and is therefore a zoonoses. Coxiella burnetii is endemic in most countries and sporadic outbreaks are often associated with infected dairy goats following abortion storms. Coxiella burnetii has been studied extensively for nearly eight decades, though Q fever pathogenesis is not fully understood and current diagnostic and preventative strategies are not reliable. The objectives of this study are to (1) detail how C. burnetii modulates host cell responses and use this information to (2) identify genetic markers that predict host resistance and (3) develop a vaccine to reduce/prevent transmission. The overall objective is to combine genetics and vaccinology to mitigate risk of C. burnettii to producers and therefore humans.
Approach:
The zoonotic intracellular bacteria Coxiella burnetii, the causative agent of Q fever in humans, has a worldwide distribution excepting only New Zealand. C. burnetii is endemic in most countries and sporadic outbreaks are often associated with infected dairy goats following abortion storms. Coxiella burnetii has been studied extensively for nearly eight decades, though Q fever pathogenesis is not fully understood and current diagnostic and preventative strategies are not reliable. For instance, over 4,000 individuals were recently infected in the Netherlands over a period of three years. In the US, there is significant divergence between Q fever seroprevalence and reported cases due to under- or misdiagnosis.
With a complicated developmental cycle, an infectious dose as low as one organism, the ability to survive high temperatures and ultraviolet light, and disseminate through the air infecting large numbers of people, C. burnetii warrants additional investigation. The host mechanisms determining C. burnetii clearance, persistence, and recrudescence in chronic Q fever are not known. Components of the innate immune system such as the Toll-like receptors (TLR)-2 and TLR-4 are known to be involved in recognition of and host response to C. burnetii. Recent findings suggest the inflammasome is also involved in host immunity. Furthermore, identifying host genetic factors that determine this response is critical for better anticipating clinical outcomes. Our specific research aims include - Aim 1: Identify the specific inflammasome complexes inhibited by Coxiella burnetii (NMII) that block caspase-1 activation and its downstream effects (cell death and release of IL1ß); and Aim 2: Identify the host genetic factors responsible for persistence of avirulent C. burnetii infection and host susceptibility. Using genetically engineered mice (GEM) and mouse macrophages we will determine if C. burnetii triggers the inflammasome cascade resulting in bacterial clearance in macrophages and if so, characterize this pathway. For Aim 2, we work with Stephen White, PhD at the USDA Field Station to perform GWAS studies to identify genes that are associated with increased resistance to C. burnetii.
